Genetic Variant NM_006012.4:c.31C>T (chr19-6361605-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006012.4(CLPP):c.31C>T(p.Arg11Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 1,261,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

CLPP
NM_006012.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.583

Publications

0 publications found

Variant links:

Genes affected

CLPP (HGNC:2084): (caseinolytic mitochondrial matrix peptidase proteolytic subunit) The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

CLPP Gene-Disease associations (from GenCC):

Perrault syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
Perrault syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLPP links:

ENSG00000269802 (HGNC:):

ENSG00000269802 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2553182).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPP	NM_006012.4	MANE Select	c.31C>T	p.Arg11Trp	missense	Exon 1 of 6	NP_006003.1	Q16740

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLPP	ENST00000245816.11	TSL:1 MANE Select	c.31C>T	p.Arg11Trp	missense	Exon 1 of 6	ENSP00000245816.3	Q16740
CLPP	ENST00000715787.1		c.31C>T	p.Arg11Trp	missense	Exon 1 of 6	ENSP00000520519.1	Q16740
CLPP	ENST00000926271.1		c.31C>T	p.Arg11Trp	missense	Exon 1 of 5	ENSP00000596330.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

50660

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000238

AC:

AN:

1261192

Hom.:

Cov.:

AF XY:

0.00000164

AC XY:

AN XY:

611040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24404

American (AMR)

AF:

0.00

AC:

AN:

16916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17474

East Asian (EAS)

AF:

0.00

AC:

AN:

29782

South Asian (SAS)

AF:

0.00

AC:

AN:

57290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4998

European-Non Finnish (NFE)

AF:

0.00000296

AC:

AN:

1014872

Other (OTH)

AF:

0.00

AC:

AN:

51734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.18

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.58

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.43

REVEL

Benign

0.11

Sift

Benign

0.062

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.26

MutPred

0.48

Loss of methylation at R11 (P = 0.0176)

MVP

0.30

MPC

0.79

ClinPred

0.49

GERP RS

1.1

PromoterAI

-0.010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.27

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over